Design and synthesis of bone-selective osteogenic oxysterol-bisphosphonate analogues

骨选择性成骨氧甾醇二膦酸酯类似物的设计与合成

• 批准号: 9046155
• 负责人: Frank Stappenbeck
• 金额: $ 49.9万
• 依托单位: MAX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046155
• 关键词: Acids; Address; Adipocytes; Adverse effects; Affect; Age; Agonist; Alendronate; Allosteric Site; American; Anabolic Agents; Animals; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Blood Circulation; Bone Density; Bone Formation Stimulation; Bone Growth; Bone Resorption; Cells; Cephalic; Chemicals; Cholesterol; Clinical; Combined Modality Therapy; Cysteine-Rich Domain; Defect; Development; Drug or chemical Tissue Distribution; Equilibrium; Erinaceidae; Evaluation; FDA approved; Family; Forteo; Fosamax; Fracture; Future; GTP-Binding Proteins; Generations; Hormonal Change; Human; Hydroxycholesterols; In Vitro; Injection of therapeutic agent; Intervention; Lead; Ligand Binding; Mediating; Menopause; Mesenchymal Stem Cells; Methods; Minerals; Modeling; Mus; Oryctolagus cuniculus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plague; Postmenopausal Osteoporosis; Process; Property; Proteins; Rattus; Reporting; Research; Risk; Safety; Site; Small Business Innovation Research Grant; Structure-Activity Relationship; Therapeutic Intervention; Tissues; Toxic effect; Vertebral column; Work; analog; base; bisphosphonate; bone; bone loss; bone metabolism; cell type; clinical investigation; cranium; cyclopamine; design; drug mechanism; effective intervention; extracellular; improved; in vitro Assay; in vitro activity; in vivo; lifestyle factors; lipid biosynthesis; mouse model; novel; older men; osteoblast differentiation; osteogenic; oxidation; phase 1 study; phase 2 study; phase 3 study; public health relevance; receptor coupling; smoothened signaling pathway; standard of care; success; targeted agent; therapeutic development

 DESCRIPTION (provided by applicant): Osteoporosis directly affects 10 million Americans and another 34 million are osteopenic and at risk for developing osteoporosis. Bisphosphonate drugs, for example alendronic acid (ALN, Fosamax), can improve bone density and reduce fracture risk by slowing osteoclastic bone resorption; however, many of the existing anti-resorptive therapies are plagued with untoward side effects and limited duration of clinical benefits. New and improved strategies for therapeutic intervention in osteoporosis are needed, particularly with new treatments that safely promote anabolic bone growth. A dual therapy approach, addressing both resorption and formation of bone could also be helpful. Presently, there is only one FDA approved bone anabolic agent, Forteo (teriparatide), that confers significant clinical benefits in osteoporosis, but its use is severely restricted due to safety concerns. Multipotent mesenchymal stem cells (MSCs) are precursors of a variety of cell types, including osteoblasts and adipocytes. Formation of new bone is driven by osteoblastic differentiation of MSCs, a process that can be thrown off balance by age, lifestyle factors and hormonal changes that occur with menopause. Parhami et al. discovered that specific oxysterols induce osteogenesis when applied to MSCs while inhibiting their adipogenesis. The most promising proprietary semi-synthetic oxysterol to date, OXY133, displays increased potency for osteogenic differentiation in vitro, including in primary rat, rabbit, and human MSCs, and it stimulates robust localized bone formation in vivo in rat and rabbit spine fusion and crania and femoral defect models. During SBIR Phase I research, we have begun evaluating drug conjugates of osteo- anabolic Oxy133 and Alendronate (ALN), a well-established anti-resorptive drug that also serves as a bone- targeting agent. We have worked out methods for chemical conjugation and characterized biophysical and biological properties of the resulting conjugates. Oxy133-ALN conjugates display strong in vitro binding to bone mineral and stimulate Hedgehog (Hh) pathway signaling and osteogenesis in MSCs. In this application, we propose to further develop Oxy133-ALN conjugates as potential dual therapy agents for osteoporosis, stimulating bone formation by osteoblasts (function of Oxy133), and inhibiting bone resorption by osteoclasts (function of ALN). Expanding on our successful Phase I studies, we propose to perform Phase II studies as part of 3 Specific Aims: Aim 1: Development of scalable methods for the synthesis of Oxy133-ALN conjugates. Aim 2: Evaluation of the inhibition of osteoclastic bone-resorption by Oxy133-ALN conjugates and the possibility of a dual therapy. Aim3: Determination of Oxy133-ALN conjugate tissue distribution properties and evaluation of select Oxy133- ALN conjugates for efficacy in an OVX mouse model.

 描述（由适用提供）：骨质疏松症直接影响1000万美国人，而另外3400万的骨质疏松症是骨质减少性的，患有骨质疏松症的风险。双膦酸盐药物，例如艾伦丁酸（Aln，Fosamax），可以通过减慢破骨碎屑骨溶液来改善骨密度并降低断裂风险。但是，许多现有的抗热疗法困扰着副作用，临床益处的持续时间有限。需要进行新的和改进的在骨质疏松症治疗干预的策略，尤其是在安全促进合成代谢骨生长的新疗法中。一种双重疗法方法，解决骨骼的分辨率和形成也可能会有所帮助。目前，只有一个FDA批准的骨合代剂Forteo（Teriparatide）承认骨质疏松症的临床益处很大，但由于安全问题，其使用受到严重限制。多态间充质干细胞（MSC）是多种细胞类型的前体，包括成骨细胞和脂肪细胞。新骨的形成是由MSC的成骨细胞分化驱动的，MSC可以按年龄，生活方式因素和更年期发生的骑马变化降低平衡。 Parhami等。发现特异性的氧醇在抑制其脂肪形成的同时诱导成骨。迄今为止，最有希望的专有半合成氧醇OXY133显示出体外成骨分化的效力，包括在初级大鼠，兔子和人类MSC中，并且它刺激了大鼠脊柱融合和兔融合以及颅骨融合以及颅骨融合以及颅骨的局部骨骼形成。在SBIR I期研究期间，我们已经开始评估骨代谢氧的药物缀合物133和Alendronate（ALN），这是一种良好的抗敏化药物，也是骨靶向剂。我们已经制定了化学共轭的方法，并表征了所得共轭物的生物物理和生物学特性。 OXY133-ALN结合物在MSC中刺激刺猬（HH）途径信号传导和成骨的体外结合，并刺激刺猬（HH）途径。在此应用中，我们建议进一步发展Oxy133-Aln共轭物作为骨质疏松症的潜在双重治疗剂，通过骨细胞（Oxy133的功能）刺激骨骼形成骨骼，并通过骨细胞抑制骨骼分辨率（ALN的功能）。在我们成功的I期研究中扩展，我们建议将II期研究作为3个特定目的的一部分：AIM 1：开发可扩展方法的合成133-Aln结合物。 AIM 2：评估Oxy133-Aln结合物对破骨骨吸附的抑制作用和双重疗法的可能性。 AIM3：确定OXY133-ALN结合组织分布的特性和评估选择Oxy133-Aln结合物在OVX小鼠模型中的效率。